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. 2021 May 21;16(5):e0251676. doi: 10.1371/journal.pone.0251676

A meta-analysis of circulating microRNAs in the diagnosis of papillary thyroid carcinoma

Yan liu 1,#, Houfa Geng 2,#, Xuekui Liu 2, Mingfeng Cao 3,*, Xinhuan Zhang 3,*
Editor: Giancarlo Troncone4
PMCID: PMC8139519  PMID: 34019567

Abstract

Background

Aim of this meta-analysis was to evaluate the overall diagnostic value of circulating mini miRNAs for papillary thyroid carcinoma (PTC) and to find the possible molecular marker with higher diagnostic value for PTC.

Methods

We searched the Pubmed, Cochrane and Embase database until June 2020. We selected relevant literatures associated with the diagnosis of PTC with circulating miRNAs. The number of cases in experimental group and the control group, sensitivity and specificity could be extracted from the literatures.

Results

We got 9 literatures including 2114 cases of PTC. Comprehensive sensitivity was 0.79, comprehensive specificity was 0.82, positive likelihood ratio was 4.3, negative likelihood ratio was 0.26, diagnostic advantage ratio was 16. The summary receiver operating characteristic curve was drawn and the Area Under the Curve was 0.87.

Conclusions

Circulating microRNAs may be promising molecular markers for the diagnosis of papillary thyroid carcinoma. Combined detection of certain serum microRNAs can improve the diagnostic accuracy of papillary thyroid carcinoma. Especially MiR-222 and miR-146b may be prime candidates for the diagnosis of PTC in Asian population.

Introduction

Thyroid cancer is a kind of common malignant tumor. The incidence of thyroid cancer ranks sixth among all malignant tumors [1]. Papillary thyroid carcinoma (PTC) is the most common histological type of thyroid cancer. To date the most reliable method to evaluate thyroid nodules is fine needle aspiration cytology (FNA), but the FNA still has its technical limitations. Less than 20% of surgically removed nodules are malignant [2–4]. Therefore, in order to improve the diagnostic accuracy of PTC and avoid unnecessary surgery, more and more researchers focused their attention to explore the molecular markers of PTC. Recent studies have shown that the abnormal expression of microRNAs (miRNAs) is closely related to the occurrence and development of tumors [5–7]. Studies have reported that thyroid cancer is associated with somatic cell mutation [8], gene expression [9], and miRNA expression [10, 11]. Many miRNAs may play an important role in the occurrence, development, metastasis and prognosis of thyroid cancer [10, 11].

MicroRNAs are a class of endogenous, small (21–23 nucleotides in length), non-coding RNAs. They can negatively regulate gene expression and regulate basic physiological processes, such as cell differentiation, growth, proliferation, metabolism and apoptosis [12, 13]. Circulating miRNAs are stable in circulation and can be detected stably from peripheral blood. These properties of miRNAs make them promising non-invasive biomarkers for cancer and other diseases. However, to date there are few studies on circulating miRNAs in PTC, and the conclusions are inconsistent. The diagnostic value of circulating miRNAs has not been accurately evaluated.

In this study, we hope to evaluate the overall diagnostic value of serum/plasma miRNAs for PTC by analyzing the research results in the existing literature and using statistical software, and try to find sensitive and specific molecular markers for the diagnosis of PTC.

Materials and methods

Literature search strategy

By searching the pubmed, Cochrane and Embase database, we searched for the literatures related to the diagnosis of thyroid papillary cancer by serum miRNA, and restricted the publication date of literature by the end of 30. Jun. 2020. Search terms were “thyroid cancer”, “papillary thyroid carcinoma”, “thyroid nodule”, “microRNA”, “miRNA”, “miR”, “serum”, “circulation”, “plasma”. The English retrieval method is {(“thyroid cancer” OR “papillary thyroid carcinoma” OR “thyroid nodules”) AND (“microRNA” OR “miRNA” OR “miR”) AND (“serum” OR “circulation” OR “plasma”)}.

Selection criteria

Inclusion criteria include: (1) Studies associated with the diagnosis of PTC by serum/plasma miRNAs. (2) The experimental groups were PTC, and the control groups were benign thyroid disease (including nodular goiter or thyroid adenoma). The age and sex of these groups were balanced and comparable. (3) The number of cases, sensitivity and specificity could be extracted from the experimental group and the control group, and table data could be calculated, including true positives (tp), false positives (fp), false negatives (fn), true negatives (tn).(4) The results of pathological examination after operation were taken as the gold standard for diagnosis. (5) The detection methods and reagent sources of miRNAs in the literature were clear. (6) No limitation on age, sex, nationality and race. The language of the literatures was English. Exclusion criteria were as follows: (1) Literature review, meetings and letters; (2) Simple descriptive study without control group; (3) Repeated literature; (4) Literatures that could not be obtained complete data.

Data extraction and management

According to inclusion and exclusion criteria, two evaluators screened literatures strictly and extracted data independently. The main data extracted from the study were: the first author, the research country, the publication time, the target miRNAs, the sample source of miRNAs, the four-grid table data (including tp, fp, fn, tn). If the results of the two evaluators were inconsistent, they would cross-check the data.

Quality assessment

QUADAS-2(Quality Assessment of Diagnostic Accuracy Studies-2) in Revman 5.3 was used to evaluate the quality of the included studies, include Patient Selection, Index Test, Reference Standard, Flow and Timing. Significant issues included “yes”, “no”, “uncertainty”. Risk level of bias are divided into “high”, “low”, “uncertainty”. Clinical applicability of selected patients, index testing and standard of reference were evaluated respectively. Two evaluators independently conducted quality evaluation, and finally cross-checked the relevant data extracted. If there were differences, they would consult the mentor.

Data synthesis and statistical analysis

The statistical software used was STATA 15.1 and Meta-disc 1.40. Firstly, the heterogeneity of the study was tested by I2 test: if I2 ≤ 50% used fixed effect model, if I2 ≥ 50% used random effect model. Statistical analysis was performed including sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio. The comprehensive working characteristic curve was drawn and the area under curve (AUC) was calculated. Additionally, the value of AUC is 0.5–0.7, 0.7–0.9, and 0.9–1.0, which represents the low, moderate, and high diagnostic efficacy, respectively. The Spearman correlation coefficient was calculated by metadisc1.40 software to evaluate the heterogeneity caused by threshold effect: if P > 0.05, there is no threshold effect, and all indicators can be combined; if P < 0.05, there is threshold effect, and the research indicators can not be combined, but simply described. Then, subgroup analysis and regression analysis were used to explore the source of heterogeneity. Sensitivity analysis was conducted to explore the robustness and reliability of the selected literatures. Finally, the Deek funnel plot was used to test the publication bias. If P < 0.10, there was publication bias.

Results

Summary of searches and study selection process

Through searching the database, 215 literatures were obtained, of which 77 literatures remained after excluding duplicated literatures. By simply reading the title and abstract, we excluded 17 literatures of reviews, conference and literatures by the same author. Following further evaluation, 51 literatures were excluded for the following reasons: literatures focusing on the prognosis and therapy (n = 13), the mechanism of occurrence (n = 12), non-serum/plasma samples (n = 18), and literatures that could not be extracted complete data (n = 8). Finally, we got 9 literatures [14–22], including 29 unique studies (part of the literatures included two or more independent studies). A total of 2114 cases of papillary thyroid carcinoma and 1615 cases of control group were included (Fig 1).

Fig 1. Flow diagram of screening studies.

Fig 1

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The basic characteristics of literature

The basic features of the literatures were listed in S1 Table. We extracted the main data from the study, including the first author, the research country, the publication time, the target miRNAs, the sample source of miRNAs, the true positives, false positives, false negatives, true negatives.

Quality evaluation results

Revman 5.3 was used to evaluate the quality of 9 articles (Fig 2). In general, the quality of the included literature was barely satisfactory. Most of the studies were case-control studies, and the reference diagnostic gold standard of all experiments was the pathological results after thyroid cancer surgery. However, Rosignolo [19] did not mention appropriate selection and exclusion criteria, which led to the risk of bias in the field of case selection is not clear. We can also see from the quality assessment diagram that the bias risk of the test to be evaluated is high, which may be related to the implementation of the test, the different process and the lack of preset threshold. Because there are few studies on the diagnosis of PTC by circulating miRNAs, most of them are based on the ROC curve to obtain the optimal diagnostic threshold, so there is no unified diagnostic threshold standard. Finally, Yu et al [14], Cantaras et al. [15], Li et al. [17] and Yu et al. [18] did not observe the expression of circulating miRNA in postoperative PTC patients, which may cause uncertainty in the part of flow and timing.

Fig 2. Quality assessment diagram.

Fig 2

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Statistical analysis results

The meta-analysis was carried out by using the Midas module in Stata 15.1. The I2 of sensitivity and specificity were 90.25 and 83.04. On account of the I2 more than 50%, we selected the random effect model in Stata to obtain meta-analysis results of circulating miRNAs in the diagnosis of PTC: comprehensive sensitivity was 0.79 [95% CI: 0.72, 0.84], comprehensive specificity was 0.82 [95% CI: 0.76, 0.86], positive likelihood ratio was 4.3 [95% CI: 3.2, 5.7], negative likelihood ratio was 0.26 [95% CI: 0.20, 0.35], diagnostic advantage ratio was 16 [95% CI: 10, 25] (Fig 3). The summary receiver operating characteristic curve (SROC) was drawn (Fig 4) and the Area Under the Curve (AUC) was 0.87 [95% CI: 0.84, 0.90].

Fig 3. Forest plot of sensitivity and specificity of circulating microRNAs in the diagnosis of papillary thyroid carcinoma.

Fig 3

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Fig 4. The summary receiver operating characteristic curve of circulating microRNAs in the diagnosis of papillary thyroid carcinoma.

Fig 4

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It was concluded that circulating miRNAs could be used as valuable molecular markers for the diagnosis of papillary thyroid carcinoma. The Spearman correlation coefficients of sensitivity logarithm and (1-specificity) logarithm (r = 0.146, p = 0.451) were calculated by meta-disc 1.40, which showed that there was no obvious threshold effect between the studies.

Subgroup analysis

Considering the heterogeneity was considerable in our meta-analysis with I2 more than 50%, subgroup analyses and meta-regression analysis were performed. The subgroup analyses was carried out according to the study area, the number of miRNAs, the types of miRNAs, the source of miRNAs samples and internal reference. We found the following results:(1) Circulating miR-222 and miR-146b may be valuable molecular markers of papillary thyroid carcinoma in Asian population. Among them, the diagnostic value of miR-222 was sensitivity: 0.60, 95% CI: 0.57–0.79; specificity: 0.90, 95% CI: 0.84–0.94; PLR: 6.8, 95% CI: 4.1–11.4; NLR: 0.34, 95% CI: 0.24–0.49; DOR: 20, 95% CI: 10–42; AUC: 0.90, 95% CI: 0.84–0.94, with high diagnostic efficacy (Fig 5a). The diagnostic value of miR-146b was sensitivity: 0.82, 95% CI: 0.60–0.93; specificity: 0.71, 95% CI: 0.60–0.79; PLR: 2.8, 95% CI: 1.8–4.2; NLR: 0.26, 95% CI: 0.10–0.66; DOR: 11, 95% CI: 3–38; AUC: 0.72, 95% CI: 0.68–0.76, with medium diagnostic effect (Fig 5b). However, there are few studies on the diagnosis of PTC by these two miRNAs in circulation. We only included three such literatures. There are 270 PTC patients in miR-222 and 234 patients in miR-146b. The included studies are few and the number of cases is not rich. Therefore, it can only provide a clue for the future research direction. At the same time, we need to further expand the sample size to verify in the future research. However, in European population, there is no relevant literature on circulating miR-222 and miR-146b for papillary thyroid carcinoma, so the diagnostic value of these two miRNAs in European population is still unclear. (2) The combination miRNA (sensitivity: 0.88, 95% CI: 0.80–0.94; specificity: 0.89, 95% CI: 0.73–0.96; PLR: 8.1, 95% CI: 3.2–20.7; NLR: 0.13, 95% CI: 0.08–0.21, DOR: 62, 95% CI: 29–136; AUC: 0.94, 95% CI: 0.92–0.96 (Fig 5c), were more valuable than single miRNA (Fig 5d). (3) It is noteworthy that serum miRNAs (AUC: 0.89, 95% CI: 0.86–0.91, Fig 5e) may be more conducive than plasma miRNAs (AUC: 0.68, 95% CI: 0.64–0.72, Fig 5f) in the diagnosis of papillary thyroid carcinoma. (4) Race also has an impact on the diagnostic value of miRNAs for papillary thyroid cancer. The diagnostic value of Europeans (AUC: 0.90, 95% CI: 0.87–0.92, Fig 5g) may be higher than that of Asians (AUC: 0.86, 95%CI: 0.83–0.89, Fig 5h). (5) The sensitivity, specificity, PLR, NLR, DOR and AUC of miR-16 were 0.80, 0.84, 5.1, 0.24, 22 and 0.89 (Fig 5i), which suggests that miR-16 as an internal reference is more helpful than other miRNAs. The comprehensive diagnostic indexes of each subgroup are shown in S2 Table. For regression analysis (Fig 6), we found that the region (P<0.001) and sample source (P<0.01) were the main sources of heterogeneity.

Fig 5. SROC curve showed the diagnostic efficacy of miR-222 (a) and mir-146b (b), miRNA combination (c) and single miRNA (d), serum miRNA (e) and plasma miRNA (f), Asia (g) and Europe (h), and mir-16 as internal reference (i).

Fig 5

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Fig 6. Regression analysis.

Fig 6

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Sensitivity analysis of the included studies was performed (Fig 7). After each exclusion of a single study, the remaining studies were recombined, and the results did not change significantly, which indicated that the sensitivity of the included studies was low, and the results were more robust and credible.

Fig 7. Sensitivity analysis.

Fig 7

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Publication bias test

Stata 15.1 was used to plot Deek funnel plot. As displayed in Fig 8, it had some asymmetry, especially in the 20th study. The p value we calculated is 0.10, which indicated a certain publication bias in the included studies.

Fig 8. Deek funnel.

Fig 8

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Discussion

Papillary thyroid carcinoma (PTC) is the most common histological type of thyroid cancer. The incidence of PTC is increasing year by year, and the number of asymptomatic thyroid micro-carcinomas (tumors with a maximum diameter less than or equal to 1 cm) is increasing.

To date the most reliable method to evaluate thyroid nodules is fine needle aspiration cytology (FNA), but the FNA still has its technical limitations. There are still exist false positive and false negative in FNA. About diagnose 20%–30% of thyroid nodules can not determined through FNA, especially for Bethesda III and IV follicular nodules, FNA can not identify the nature of nodules, which may led to the surgical treatment of some nodules that did not need surgical resection.

MicroRNAs (miRNAs) are highly conserved non-coding single-stranded small RNA molecules, which participate in cell proliferation, differentiation and apoptosis [23]. Post-transcriptional regulation mediated by microRNAs is an important way to regulate gene expression. The mutation or abnormality of microRNAs plays a key role in the occurrence, development, invasion and metastasis of tumors [24], and it is closely related to the therapeutic response, staging, prognosis and recurrence detection of tumors [25]. Because of the good stability of miRNAs in peripheral blood, the detection of miRNAs is noninvasive, sensitive and simple, which has become a hot topic in molecular biology of tumors in recent years [26]. Increasing studies have found that circulating microRNAs can be used as molecular markers for a variety of diseases especially in malignant tumor. Our study also found that miR-222 and mir-146b have high specificity in the diagnosis of papillary thyroidcarcinoma. So Combined detection of microRNA in circulating and cytopathology specimens may greatly improve the diagnostic accuracy of thyroid cancer.

Our study mainly discussed the diagnostic value of circulating miRNAs in PTC. Meta analysis showed that the total sensitivity was 79%, and the total specificity was 82%. The positive likelihood ratio was 4.3, which showed that the positive rate of circulating miRNAs in PTC patients was 4.3 times higher than that in patients with benign group. The overall diagnostic ratio was 16 as well as the negative likelihood ratio was 0.26, suggesting that circulating miRNAs may have a good diagnostic ability for PTC. Commonly, the area under the ROC curve was used to estimate the accuracy of diagnosis, ROC curve area at 0.7 to 0.9 indicating the index has a higher accuracy; area above 0.9 indicating the index has the highest accuracy. In our study, the AUC was 0.87, which showed that circulating miRNAs may have a promising diagnostic value for PTC.

In our study, 20 kinds of microRNAs were included. Several kinds of microRNAs have been studied many times, including miRNA-146b, miRNA-221, miRNA-222. Subgroup analysis of microRNA type showed that miRNA-222 and miRNA-146b had high diagnostic value, especially the miRNA-222. The sensitivity, specificity and diagnostic ratio of miRNA-222 were 0.70, 0.90 and 22.55 respectively. MiRNA-222, locates on chromosome Xp11.3 [27], it is a well-defined proto-oncogene family. It is abnormally expressed in many tumors, such as primary hepatocellular carcinoma and pancreatic cancer [28]. In this study, we only included three literatures about the relationship between miRNA222 and papillary thyroid carcinoma. The number of literatures was limited, which need to be verified by high-quality and larger sample studies. From the subgroup analysis, we could also find that the diagnostic value of microRNAs in serum samples may be higher than that in plasma samples for PTC, which indicated that we could pay more attention to serum samples in the future. Compared with plasma, the absence of some coagulation factors and fibrinogen in serum may reduce the interference factors in the determination of circulating microRNAs. In addition, some studies have found that a large number of cytokines can release during the process of activation and destruction of platelets, which may affect the determination results. However, there are few literatures discuss it, and more further researches are needed to explore the expression differences between serum and plasma microRNAs and their possible reasons and significance [29].

Subgroup analysis of the number of miRNAs showed that sensitivity, specificity and diagnostic ratio of the combined miRNAs were 0.87, 0.82, 64.58, which was higher than that of single miRNAs in the diagnosis of PTC. So it is more important to pay more attention to the specific combined detection of miRNAs than single circulating miRNA, in order to better diagnosis of PTC and reduce unnecessary surgery.

At present, real-time fluorescent quantitative (RT-qPCR) has been widely used in the studies of the mRNA, the detection of DNA, the determination of single nucleotide polymorphism and so on [30, 31]. Due to the advantages of it such as high sensitivity, good repeatability, accurate quantification and so on, it is also widely used in the detection of circulating miRNAs. Among the included literatures, some literatures initially used gene microRNA array to screen miRNAs differently expressed between groups, followed by qPCR amplification after reverse transcription into cDNA. The development of RT-qPCR has accelerated the development of miRNAs in cancer diagnosis and treatment.

Limitations of our study include the following aspects: Firstly, the bias risk of the index test in the literature was higher, which may be related to the different method of the study design, the implementation process of test and the absence of pre-set threshold. To date, there are few studies on the diagnosis of PTC by miRNAs. Most of the studies got the best diagnostic threshold based on the ROC curve. There was no unified diagnostic threshold standard, so the bias risk of the index test was higher. Secondly, the meta-analysis had great heterogeneity. We had not found the source of heterogeneity through subgroup analysis. The possible reasons for the heterogeneity may be as follows: age, sex, number of lesions, capsular invasion, lymph node metastasis and stage of papillary thyroid carcinoma in the experimental group were different; design, detection methods and reagent selection of different studies were inconsistent; the cut-off values used were different. Thirdly, we could see from the funnel plot that it had certain asymmetry, especially in the 20th study. We review the source of the literature: Silvia Cantara et al. have identified for the first time of two miRNAs differently expressed in serum of PTC patients in a caucasian population. They found that the best diagnostic accuracy was miRNA95 with a sensitivity of 94.9% and a specificity of 98.7%. Its sensitivity and specificity were significantly higher than any other microRNAs we included, which may be the reason why it deviated from the reference line on the funnel plot. Therefore, this requires us to further expand the sample size in future research to verify the diagnostic value of microRNA95 for PTC in a Caucasus population. Overall, we thought the result of publication bias testing was still acceptable.

Conclusion

Circulating microRNAs may be promising molecular markers for the diagnosis of papillary thyroid carcinoma. Especially MiR-222 and miR-146b may be prime candidates for the diagnosis of papillary thyroid carcinoma in Asian population,. Combined detection of certain serum microRNAs can improve the diagnostic accuracy of papillary thyroid carcinoma.

Supporting information

S1 Table. The basic characteristics of inclusion literatures.

(PDF)

Click here for additional data file. (81.5KB, pdf)
S2 Table. Subgroup analysis of circulating microRNAs in the diagnosis of PTC.

(PDF)

Click here for additional data file. (62.3KB, pdf)
S1 File. Prisma checklist.

(PDF)

Click here for additional data file. (140.7KB, pdf)
S2 File. Search strategy and search terms of this manuscript.

(PDF)

Click here for additional data file. (33.7KB, pdf)

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

This work was supported by the Higher Educational Science and Technology Program of Shandong Province, China (Grant No. J17KA246); Natural Science Foundation of Shandong Province of China (Grant No. ZR2017LH023); Medical and Health Project of Shandong Province, China (Grant No. 2015WS0096), Science and Education Project for Young Medical Talents, Jiangsu Province, China (Grant No.QNRC2016388), as well as Academic Promotion Program of Shandong First Medical University (Grant No. 2019QL017).

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Decision Letter 0

Giancarlo Troncone

1 Feb 2021

PONE-D-20-40536

A meta-analysis of circulating microRNAs in the diagnosis of papillary thyroid carcinoma

PLOS ONE

Dear Dr. Huan Xin Zhang,,

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Giancarlo Troncone

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The paper by Zhang entitled A meta-analysis of circulating microRNAs in the diagnosis of papillary thyroid

carcinoma covers an interesting subject. I suggest only minor text editing. In particular (line 37 page 2) the Authors affirms that "Less than 20% of surgically removed nodules are malignant". However, this statement it is correct only if it is referred to the FN/SFN Bethesda category. Indeed, I suggest to discuss in brief both the limit of FNA in particular in indeterminate categories and the use of miRNA in thyroid cytopathology specimens.

Reviewer #2: The manuscript entitled "A meta-analysis of circulating microRNAs in the diagnosis of papillary thyroid carcinoma" highlighted that circulating microRNAs may be promising molecular markers for the diagnosis of 22 papillary thyroid carcinoma.

- The manuscript may benefit from a language revision by an English native speaker.

- The Authors should provide better quality figures.

- The Authors should address how selection bias have been solved.

- The Authors should better discuss if there are any difference in the role of serum and plasma extracted miRNAs in the diagnosis of PTC.

- The Authors should provide the extensive forms for all acronyms through the text when they first appear.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 May 21;16(5):e0251676. doi: 10.1371/journal.pone.0251676.r002

Author response to Decision Letter 0

22 Mar 2021

Point-to-point Reply to the comments

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found athttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdfhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Reply: Thank you for your suggestions. In the revised manuscript, we modified the paper style include title, reference and so on to meet the PLOS One’s requirements.

2. At this time, we ask that you please provide the full search strategy and search terms for at least one database used as Supplementary Information.

Reply: Thank you for your careful comments. Full search strategy and search terms of this manuscript were sumarized in the supplement file 1.

3. Thank you for including the statement that "The database search was conducted on XXXXXX". Please revise this statement to clarify whether all databases were searched from inception, or if there were any limits placed on the publication dates in your search.

Reply: Thank you for your professional suggestions. We revised the statement and added the limits placed on the publication dates in page 4 line 71 to line 73 of the paper.

4. Please ensure you have thoroughly discussed any potential limitations of this study within the Discussion section, including the potential impact of confounding factors.

Reply: Thank you for your consideration suggestion. We have revised the discussion section according to your suggestion in page 11 line 228 to line 232 and page 12 line 241 to line 245 as well as page 13 line 268 to line 274 in the revised paper

5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

Reply: Thank you for your suggestions. This manuscrpt’s database were acquired from the published literatures, and the database were all showed in the article. Search strategy has been provided in the supporting data. At the same time, we deleted the Data Availability Statement at the end of the paper.

6. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

Reply: We are so sorry for our negligence. In the revised version of the manuscript, we carefully re-check each Funding Information and revised them. But we can't change the information of fundings in the financial disclosure section. We have 5 fundings, which have been listed in detail at the end of the manuscript. However, only 4 fundings are displayed in the financial disclosure section, and we can't find a dialog box that can be modified. We would be greatly appreciated you for your consideration to help me update the information in financial disclosure section. We have request the updating of fundings in cover letter.

7. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

Reply: Thank you for your suggestions. I have registered ORCID ID number in your magazine, it is 0000-0002-9729-8995. I have updated my Information and authenticated the pre-existing iD in Editorial Manager, now, it has been validated in my Editorial Manager account.

8. Reviewer #1: The paper by Zhang entitled A meta-analysis of circulating microRNAs in the diagnosis of papillary thyroidcarcinoma covers an interesting subject. I suggest only minor text editing. In particular (line 37 page 2) the Authors affirms that "Less than 20% of surgically removed nodules are malignant". However, this statement it is correct only if it is referred to the FN/SFN Bethesda category. Indeed, I suggest to discuss in brief both the limit of FNA in particular in indeterminate categories and the use of miRNA in thyroid cytopathology specimens.

Reply: Thank you for your insightful comments. According to your opinion, we discussed the the limit of FNA in indetermination particular categories and the use of miRNA in thyroid cytopathology specimens in page 11-12 from line 241 to line 245.

9. Reviewer #2: The manuscript entitled "A meta-analysis of circulating microRNAs in the diagnosis of papillary thyroid carcinoma" highlighted that circulating microRNAs may be promising molecular markers for the diagnosis of papillary thyroid carcinoma.

9.1 The manuscript may benefit from a language revision by an English native speaker.

Reply: Thank you for your suggestions. The language of this manuscript was revised by an English native speaker. We hope that the revisions in the current manuscript will be sufficient for consideration of publication in ‘‘PLOS ONE

9.2 The Authors should provide better quality figures.

Reply: Thank you for your suggestions. In the revised version, we resubmit the new figures with higher resolution, we hope that it can meet the requirements of “PloS one”

9.3 The Authors should address how selection bias have been solved.

Reply: Thanks for your professional suggestion.9 literatures including 29 studies were analyzed in this study. The literatures were from Asian and European, and the heterogeneity test shows the I2 is very high (84%~90%). Higher heterogeneity which may be a selection bias, and may can influence the results, we used subgroup analysis to reduce the heterogeneity. The details are in the section of “subgroup analysis”.

9.4 The Authors should better discuss if there are any differences in the role of serum and plasma extracted miRNAs in the diagnosis of PTC.

Reply: Thanks for your thoughtful suggestion. We have revised the discussion section according to your suggestion in page 13 line 268 to line 274 in the revised paper

9.5 The Authors should provide the extensive forms for all acronyms through the text when they first appear.

Reply: Thank you for your careful comments. We have provided the extensive forms for all acronyms through the text when they first appear through the whole revised paper according to your suggestion.

Decision Letter 1

Giancarlo Troncone

30 Apr 2021

A meta-analysis of circulating microRNAs in the diagnosis of papillary thyroid carcinoma

PONE-D-20-40536R1

Dear Dr. Huan Xin Zhang

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Giancarlo Troncone

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have no further comments to make. The Authors have addressed all the points raised by the reviewers.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Acceptance letter

Giancarlo Troncone

12 May 2021

PONE-D-20-40536R1

A meta-analysis of circulating microRNAs in the diagnosis of papillary thyroid carcinoma

Dear Dr. Zhang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Giancarlo Troncone

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. The basic characteristics of inclusion literatures.

    (PDF)

    Click here for additional data file. (81.5KB, pdf)
    S2 Table. Subgroup analysis of circulating microRNAs in the diagnosis of PTC.

    (PDF)

    Click here for additional data file. (62.3KB, pdf)
    S1 File. Prisma checklist.

    (PDF)

    Click here for additional data file. (140.7KB, pdf)
    S2 File. Search strategy and search terms of this manuscript.

    (PDF)

    Click here for additional data file. (33.7KB, pdf)

    Data Availability Statement

    All relevant data are within the paper and its Supporting information files.

    Articles from PLoS ONE are provided here courtesy of PLOS

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